Structural Insights into Separase Architecture and Substrate Recognition through Computational Modelling of Caspase-Like and Death Domains

Winter, Anja; Schmid, Ralf; Bayliss, Richard; Fetrow, Jacquelyn S.

doi:10.1371/journal.pcbi.1004548

Title: Structural Insights into Separase Architecture and Substrate Recognition through Computational Modelling of Caspase-Like and Death Domains

Journal Article · Thu Oct 29 00:00:00 EDT 2015 · PLoS Computational Biology (Online)

DOI:https://doi.org/10.1371/journal.pcbi.1004548· OSTI ID:1233331

Winter, Anja ^[1]; Schmid, Ralf ^[1]; Bayliss, Richard ^[1]; Fetrow, Jacquelyn S. ^[2]

Univ. of Leicester (United Kingdom)
Wake Forest Univ., Winston-Salem, NC (United States)

Separases are large proteins that mediate sister chromatid disjunction in all eukaryotes. They belong to clan CD of cysteine peptidases and contain a well-conserved C-terminal catalytic protease domain similar to caspases and gingipains. However, unlike other well-characterized groups of clan CD peptidases, there are no high-resolution structures of separases and the details of their regulation and substrate recognition are poorly understood. Here we undertook an in-depth bioinformatical analysis of separases from different species with respect to their similarity in amino acid sequence and protein fold in comparison to caspases, MALT-1 proteins (mucosa-associated lymphoidtissue lymphoma translocation protein 1) and gingipain-R. A comparative model of the single C-terminal caspase-like domain in separase from C. elegans suggests similar binding modes of substrate peptides between these protein subfamilies, and enables differences in substrate specificity of separase proteins to be rationalised. We also modelled a newly identified putative death domain, located N-terminal to the caspase-like domain. The surface features of this domain identify potential sites of protein-protein interactions. Notably, we identified a novel conserved region with the consensus sequence WWxxRxxLD predicted to be exposed on the surface of the death domain, which we termed the WR motif. We envisage that findings from our study will guide structural and functional studies of this important protein family.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: Cancer Research UK

Grant/Contract Number:: C24461/A12772

OSTI ID:: 1233331

Journal Information:: PLoS Computational Biology (Online), Vol. 11, Issue 10; ISSN 1553-7358

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 15 works

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